Neuronal degeneration has been proposed to cause neurological and/or neuropsychiatric disorders (e.g., schizophrenia, Alzheimer's dementia, hepatic encephalopathy, and Parkinson's disease). Our research goal is to investigate the pathophysiological role of reactive oxygen species in degenerative brain disorders. Animal models are developed and used for studying neuro-degenerative processes and neuroprotective strategies on brain dopaminergic neurons in vivo. In vitro methods for the detection of free radical generation and the brain lipid peroxidation are also used to investigate underlying neurotoxic and/or neuroprotective mechanisms. We have demonstrated that brain neurons are vulnerable to oxidative stress caused by iron but not copper and zinc. In fact, intranigral infusion of ferrous citrate creates a parkinsonian animal model because it acutely increases dopamine overflow and chronically depletes dopamine levels. We discovered that iron-induced oxidative brain injury was protected by treatment with typical and atypical antioxidants (e.g., U-78517F, a-lipoic acid, manganese and S-nitrosoglutathione). Further in vitro results indicate that these antioxidants indeed inhibit the generation of free radicals and the peroxidation of brain lipids. The present in vivo neuroprotective results of manganese are somewhat at odds with current concepts on the pathogenesis of Parkinson's disease. In fact, manganese exposure induces pallidum injury and psychosis rather than the previously proposed nigral injury and parkinsonism. Our new finding that S-nitrosoglutathione is approximately 100-fold more potent than the classical antioxidant glutathione could have important implications for understanding the antioxidative role of nitric oxide and cellular defense systems in the brain.